Inflammation and immunomodulation in central nervous system injury - B cells as a novel therapeutic opportunity.

Acute injury to the central nervous system (CNS) remains a complex and challenging clinical need. CNS injury initiates a dynamic neuroinflammatory response, mediated by both resident and infiltrating immune cells. Following the primary injury, dysregulated inflammatory cascades have been implicated in sustaining a pro-inflammatory microenvironment, driving secondary neurodegeneration and the development of lasting neurological dysfunction. Due to the multifaceted nature of CNS injury, clinically effective therapies for conditions such as traumatic brain injury (TBI), spinal cord injury (SCI), and stroke have proven challenging to develop. No therapeutics that adequately address the chronic inflammatory component of secondary CNS injury are currently available. Recently, B lymphocytes have gained increasing appreciation for their role in maintaining immune homeostasis and regulating inflammatory responses in the context of tissue injury. Here we review the neuroinflammatory response to CNS injury with particular focus on the underexplored role of B cells and summarize recent results on the use of purified B lymphocytes as a novel immunomodulatory therapeutic for tissue injury, particularly in the CNS.

B cell treatment promotes a neuroprotective microenvironment after traumatic brain injury through reciprocal immunomodulation with infiltrating peripheral myeloid cells.

Traumatic brain injury (TBI) remains a major cause of death and severe disability worldwide. We found previously that treatment with exogenous naïve B cells was associated with structural and functional neuroprotection after TBI. Here, we used a mouse model of unilateral controlled cortical contusion TBI to investigate cellular mechanisms of immunomodulation associated with intraparenchymal delivery of mature naïve B lymphocytes at the time of injury. Exogenous B cells showed a complex time-dependent response in the injury microenvironment, including significantly increased expression of IL-10, IL-35, and TGFß, but also IL-2, IL-6, and TNFα. After 10 days in situ, B cell subsets expressing IL-10 or TGFß dominated. Immune infiltration into the injury predominantly comprised myeloid cells, and B cell treatment did not alter overall numbers of infiltrating cells. In the presence of B cells, significantly more infiltrating myeloid cells produced IL-10, TGFß, and IL-35, and fewer produced TNFα, interferon-γ and IL-6 as compared to controls, up to 2 months post-TBI. B cell treatment significantly increased the proportion of CD206+ infiltrating monocytes/macrophages and reduced the relative proportion of activated microglia starting at 4 days and up to 2 months post-injury. Ablation of peripheral monocytes with clodronate liposomes showed that infiltrating peripheral monocytes/macrophages are required for inducing the regulatory phenotype in exogenous B cells. Reciprocally, B cells specifically reduced the expression of inflammatory cytokines in infiltrating Ly6C+ monocytes/macrophages. These data support the hypothesis that peripheral myeloid cells, particularly infiltrating monocyte/macrophages, are key mediators of the neuroprotective immunomodulatory effects observed after B cell treatment.

Dopaminergic Cell Replacement for Parkinson's Disease: Addressing the Intracranial Delivery Hurdle.

Parkinson's disease (PD) is an increasingly prevalent neurological disorder, affecting more than 8.5 million individuals worldwide. α-Synucleinopathy in PD is considered to cause dopaminergic neuronal loss in the substantia nigra, resulting in characteristic motor dysfunction that is the target for current medical and surgical therapies. Standard treatment for PD has remained unchanged for several decades and does not alter disease progression. Furthermore, symptomatic therapies for PD are limited by issues surrounding long-term efficacy and side effects. Cell replacement therapy (CRT) presents an alternative approach that has the potential to restore striatal dopaminergic input and ameliorate debilitating motor symptoms in PD. Despite promising pre-clinical data, CRT has demonstrated mixed success clinically. Recent advances in graft biology have renewed interest in the field, resulting in several worldwide ongoing clinical trials. However, factors surrounding the effective neurosurgical delivery of cell grafts have remained under-studied, despite their significant potential to influence therapeutic outcomes. Here, we focus on the key neurosurgical factors to consider for the clinical translation of CRT. We review the instruments that have been used for cell graft delivery, highlighting current features and limitations, while discussing how future devices could address these challenges. Finally, we review other novel developments that may enhance graft accessibility, delivery, and efficacy. Challenges surrounding neurosurgical delivery may critically contribute to the success of CRT, so it is crucial that we address these issues to ensure that CRT does not falter at the final hurdle.

Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application.

Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.

Benefits of rapid deployment aortic valve replacement with a mini upper sternotomy.

BACKGROUND: Surgical aortic valve replacement (AVR) is currently deemed the gold standard of care for patients with severe aortic stenosis. Currently, most AVRs are safely performed through a full median sternotomy approach. With an increasingly elderly and high-risk patient population, major advances in valve technology and surgical technique have been introduced to reduce perioperative risk and post-operative complications associated with the full sternotomy approach, in order to ensure surgical AVR remains the gold standard. For example, minimally invasive approaches (most commonly via mini sternotomy) have been developed to improve patient outcomes. The advent of rapid deployment valve technology has also been shown to improve morbidity and mortality by reducing cardiopulmonary bypass and aortic cross-clamp times, as well as facilitating the use of minimal access approaches. Rapid deployment valves were introduced into our department at the Royal Infirmary of Edinburgh in 2014. The aim of this study is to investigate if utilising the combination of rapid deployment valves and a mini sternotomy minimally invasive approach resulted in improved outcomes in various patient subgroups. METHODS: Over a 3-year period, we identified 714 patients who underwent isolated AVR in our centre. They were divided into two groups: 61 patients (8.5%) were identified who received rapid deployment AVR via J-shaped mini upper sternotomy (MIRDAVR group), whilst 653 patients (91.5%) were identified who received either a full sternotomy (using a conventional prosthesis or rapid deployment valve) or minimally invasive approach using a conventional valve (CONVAVR group). We retrospectively analysed data from our cardiac surgery database, including pre-operative demographics, intraoperative times and postoperative outcomes. Outcomes were also compared in two different subgroups: octogenarians and high-risk patients. RESULTS: Pre-operative demographics showed that there were significantly more female and elderly patients in the MIRDAVR group. The MIRDAVR group had significantly reduced cardiopulmonary bypass (63.7 min vs. 104 min, p = 0.0001) and aortic cross-clamp times (47.3 min vs. 80.1 min, p = 0.0001) compared to the CONVAVR group. These results were particularly significant in the octogenarian population, who also had a reduced length of ICU stay (30.9 h vs. 65.6 h, p = 0.049). In high-risk patients (i.e. logistic EuroSCORE I > 10%), minimally invasive-rapid deployment aortic valve replacement is still beneficial and is also characterized by significantly shorter cardiopulmonary bypass time (69.1 min vs. 96.1 min, p = 0.03). However, post-operative correlations, such as length of ICU stay, become no more significant, likely due to serious co-morbidities in this patient group. CONCLUSION: We have demonstrated that minimally invasive rapid deployment aortic valve replacement is associated with significantly reduced cardiopulmonary bypass and aortic cross-clamp times. This correlation is much stronger in the octogenarian population, who were also found to have significantly reduced length of ICU stay. Our study raises the suggestion that this approach should be utilised more frequently in clinical practice, particularly in octogenarian patients.